The long term objective is to elucidate the molecular mechanisms involved in maintaining fidelity during the replication of the cell. Specific approaches addressing this question include; 1 - The biochemical investigation of mutants which have defects in DNA replication resulting in abnormal spontaneous mutation rates. 2 - The use of new nucleotide analogues to examine the biochemical mechanisms employed in discriminating correct from incorrect DNA copy. 3 - The purification and characterization of proteins (enzymes) which may be involved in maintaining fidelity either directly by acting as part of the replication complex, or indirectly by affecting other aspects of cellular metabolism such as nucleotide pool sizes. An elucidation of the factors involved in assuring the faithful replication of DNA is basic to an understanding of normal cell multiplication. The implication of somatic and germ cell mutations in human disease is already well-documented and continues to emerge. Most likely, an understanding of the biochemistry of error prevention and correction during replication will lead to a more rational approach to the prevention and treatment of these diseases.